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Gene & Protein in Disease RUNX1 gene in female-related cancers

patterning and runted embryos was called runt. Later, promoters and first exons often become hypermethylated.
Gergen et al. cloned the Drosophila segmentation gene Aberrant DNA methylation is also implicated in the
runt . Although the protein encoded by runt was development of chemotherapeutic resistance. It occurs
[26]
demonstrated to exhibit nuclear translocation, its role as in ovarian cancer and contributes to carcinogenesis and
a transcription factor was yet to be established. Eventually, chemoresistance pathways. In a study, RUNX1 gene was
in 1991, the human RUNX1 gene was cloned and observed significantly hypomethylated and overexpressed in post-
to be rearranged from t(8;21)(q22;q22) AML patients in chemotherapy (CT) primary cultures of ovarian cancer
leukemic cell DNAs . However, the role of the human patients . Using a similar approach (methylated DNA
[33]
[27]
RUNX1 gene had not been identified. The function of the immunoprecipitation coupled to CpG island tiling arrays),
RUNX1 gene was discovered shortly after the discovery of the study demonstrated that DNA hypermethylation occurs
Drosophila runt protein and human RUNX1 protein. As a in less invasive/early stages of ovarian tumorigenesis.
sequence-specific DNA-binding protein that monitored the In contrast, advanced disease has been found to be
disease specificity of the Moloney murine leukemia virus, associated with DNA hypomethylation of several oncogenes
RUNX1 was purified. Besides, Ito et al. purified RUNX2, involved in cancer progression, invasion/metastasis, and
the RUNX1 homolog. Two subunits, a DNA-binding CBF likely chemoresistance . Moreover, according to a study,
[34]
alpha chain (RUNX1 or RUNX2) and a non-DNA-binding mutations were observed in RUNX1 and CBFB genes, in
subunit termed core binding factor β (CBFβ), were purified which about 8 RUNX1 mutations were seen within the RUNX1
transcription factors; the binding capacity of RUNX1 and coding region in breast cancer cases . The runt domain,
[35]
RUNX2 was significantly enhanced by the interaction with which is crucial for DNA binding and heterodimerization,
CBFβ .
[28]
has all six missense mutations, with four mutations occurring
2. RUNX1 gene at two mutation hotspots (amino-acid positions 174 and
139/141/142). Notably, all RUNX1 mutations associated with
2.1. Background of RUNX1 gene breast cancer appear to result in loss-of-function mutants .
[36]
The human RUNX1 gene is 260 kilobases (kb) long and 2.2. Functions of RUNX1 gene
is found on chromosome 21 (21q22.12) . The gene
[29]
can be transcribed from either promoter 1 (distal) or Almost all adult mammalian, blood cells develop from
promoter 2 (proximal). As a result of alternative splicing, HSCs in the bone marrow. HSCs are cells that may engraft
multiple RUNX1 isoforms can be generated. The exons adult transplant patients and develop from immature
encode the full-length RUNX1 protein . There are two HSC precursors, which are known as pre-HSC. RUNX1
[30]
distinct domains among the exons: the runt homology is required for the development of all embryonic blood
domain (RHD) or runt domain (exons 2, 3, and 4) and the cell lineages . The trigeminal and dorsal root ganglia
[27]
transactivation domain (TAD) (exon 6). RUNX1 requires include nociceptors, specialized primary sensory neurons
these domains to facilitate DNA binding and protein- with high stimulus thresholds, and cell bodies. They
protein interactions, respectively. RUNX1 protein has 453 express various ion channels that convert mechanical,
amino acids. The runt domain (residues 50 – 177), which thermal, or chemical inputs into electrical activity .
[37]
is homologous to the p53 family, encodes its DNA-binding Several transcription factors regulate the growth of
capabilities as a transcription factor (TF) . nociceptive sensory neurons. These runt proteins regulate
[13]
developmental events by interacting with a common
RUNX1 is mutated in 4.26% of breast cancer patients, [38]
with 1.55% of all breast cancer patients having RUNX1 cofactor called CBF . The trigeminal and dorsal root
ganglia both express RUNX1 and RUNX3. The RUNX1
mutation . RUNX1 is mutated in 0.82% of ovarian gene is responsible for coordinating the phenotypic of a
[31]
cancer patients, with RUNX1 mutation present in large number of nociceptors .
[39]
0.56% of all ovarian cancer patients . The disruption
[32]
of gene regulation, which results in the loss or gain of In adult skin, RUNX1 regulates the activation and
genetic function, is known to play a significant role proliferation of hair follicle stem cells (HFSCs). RUNX1
in carcinogenesis. The addition of a methyl group is found in three types of embryonic skin precursors:
to cytosine-5 position within the context of a CpG short-term hair follicle (HF) progenitors, adult HFSCs,
dinucleotide, mediated by DNA methyltransferases, is the and mesenchymal progenitors . RUNX1 gene is
[40]
most studied epigenetic modification. The natural control required for the development of adult HFSCs and short-
of DNA methylation is disrupted in cancer, resulting term progenitors in the embryonic epithelium, but it is
in dramatic alterations in the distribution pattern of not required either. The RUNX1 gene is rigidly sought
5-methylcytosine. Heavy methylation in most chromatin in the embryonic mesenchyme for proper adult HFSC
is restricted, but unmethylated CpG islands in gene differentiation and long-term skin functioning (Table 1).
[41]
Volume 1 Issue 2 (2022) 3 https://doi.org/10.36922/gpd.v1i2.147